The compound (+)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol, also known as MDL 100,907, is a potent 5HT.sub.2A receptor antagonist which is being evaluated in the clinic for treatment of schizophrenia. J. Pharm. Exp. Ther. 277:968-9881 (1996) incorporated herein by reference. It was described in U.S. Pat. No. 5,134,149, incorporated herein by reference.
MDL 100,907 antagonizes the effects of serotonin at the 5HT.sub.2A receptor and thus is useful for treating a variety of conditions. However, this compound may also act directly or indirectly act to achieve therapeutic effects other than by its 5HT.sub.2A antagonism. For example, see European Journal of Pharmacology 273: 273-279 (1995) where MDL 100,907 has been shown to exert a tonic inhibitory influence on dopamine efflux in the medial prefrontal cortex.
An object of the present invention is to provide a new compound which after administration, releases a therapeutically effective amount of MDL 100,907 over an extended period of time. The extended period of time means a time longer than a single dose of MDL 100,907, and would last for several days, several weeks, about one month up to about 6 to about 8 weeks, and preferably from about 2 weeks to about one month.
There are many advantages to administering a single dose of a compound to a patient which lasts over an extended period of time. It can avoid compliance problems which can be particularly important in patients suffering from psychoses or addictive behaviors such as schizophrenia, obsessive compulsive behavior, depression, anxiety, anorexia and drug addiction. Other advantages include an absence of the typical oscillations of drug level achieved with multiple dose therapy through which the patient should experience an improved efficacy in treatment with lower peak drug concentrations.
While the concept of sustained release formulations is not new, not all compounds are capable of being chemically altered to produce a new compound capable of being metabolized into the active ingredient at a desirable rate and over the desired length of time. Other factors contribute to the difficulty of preparing a sustained release formulation such as protein binding and other physiological processes which can affect the therapeutic effect of the active ingredient, see for example Biochemical Pharmacology, Vol. 36, No. 10 pp1715-1722 (1987), incorporated herein by reference. Also, the chemically altered compound must be compatible with pharmaceutically acceptable carriers and be stable enough not to substantially degrade on the shelf to the active ingredient. In short, the design of an acceptable sustained release formulation is a difficult, unpredictable task.